The discovery that certain RNAs possess enzymatic activity has led to a search for applications of "ribozymes" ranging from new pharmaceuticals, e.g. Sarver et al., Science, Vol. 247, pp. 1222-1225 (1990), to new tools for molecular biology, e.g. Haseloff et al., Nature, Vol. 334, pp. 585-591 (1988); Cech et al., U.S. Pat. No. 4,987,071; and Ellington et al., Nature, Vol. 346, pp. 818-822 (1990). This increased interest in RNA applications has generated a demand for more effective methods of chemically synthesizing RNA polymers. Unfortunately, progress in the chemical synthesis of RNA has not been as rapid as that for the chemical synthesis of DNA, largely because of the constraints imposed by having to protect the extra hydroxyl attached to the 2' carbon of the ribonucleosides, e.g. Van Boom et al., pp. 153-183, in Gait, ed. Oligonucleotide Synthesis: A Practical Approach (IRL Press, Washington, D.C., 1984).
Presently, solid phase approaches provide the most effective means for chemical synthesis of RNA. Such methods proceed by the step-wise addition of protected ribonucleoside phosphoramidite or hydrogen phosphonate monomers to a growing RNA chain attached to a solid phase support, e.g. Scaringe et al., Nucleic Acids Research, Vol. 18, pp. 5433-5441 (1990); Wu et al., Tetrahedron Letters, Vol. 29, pp. 4249-4252 (1988); Wu et al., Nucleic Acids Research, Vol. 17, pp. 3501-3517 (1989); Stawinski et al., Nucleic Acids Research, Vol. 16, pp. 9285-9298 (1988). An important advance in solid phase RNA synthesis came with the introduction of alkylsilyl protection groups, e.g. t-butyldimethylsilyl(TBDMS), for the 2'-hydroxyl position, e.g. Ogilvie et al., Can. J. Chem., Vol 57, pp. 2230-2238 (1979). Difficulties still remains, however, because of the lability of the alkylsilyl groups under commonly used base deprotection conditions. Base protection groups, such as benzoyl, isobutyryl, and the like, are removed under relatively harsh basic conditions, e.g. 3:1 ammonium hydroxide-ethanol for 18 h at 55.degree. C. that can lead to the removal of a small but significant fraction of alkylsilyl protection groups, e.g. Wu et al. Nucleic Acids Research (cited above). With the 2'-hydroxyl unprotected, a small but significant fraction of the freshly synthesized RNA chains will be cleaved, resulting in a drop in yield of full length chains. If milder base deprotection conditions are employed, deprotection could be incomplete resulting in a drop in yield of biologically active material because of the interfering base protection groups remaining on the RNA chain.